Global HIV Drug Therapies and Mitochondrial Complications and Mechanisms

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DESCRIPTION (provided by applicant): Lipoatrophy and other toxicities due to mitochondrial (mt) dysfunction are common complications seen with the nucleoside reverse transcriptase inhibitors (NRTIs). As hypertriglyceridemia and insulin resistance are also frequently observed in association with lipoatrophy; the use of d4T or ZDV may also increase cardiovascular risk in patients treated with these medications. Despite their toxicities, these NRTIs are widely used components of antiretroviral (ARV) regimens used in developing countries. Even in the United States, ZDV together with lamivudine (3TC) continue to be listed as one of the preferred initial ARV regimens by the Department of Health and Human Services. Therefore, understanding the pathogenic mechanisms underlying the development of these mt toxicities are important to finding appropriate ways to monitor and prevent or minimize the complications of these medications. The University of Hawaii in collaboration with the Thai Red Cross AIDS Research Centre intends to launch a longitudinal 72 week prospective, randomized clinical trial in Bangkok, Thailand assessing the relative toxicities of short-term d4T (24 week) use followed by ZDV (n=50) compared to continuous ZDV + 3TC (n=50) or tenofovir (TDF) + emtricitabine (FTC) (n=50), all given with nevirapine (NVP) in 150 HIV+ na¿ve patients. The clinical trial will be predominantly funded by the Thai Ministry of Public Health as this trial is important to its national ARV treatment policies. We hypothesize that the mt toxicities of these medications are driven primarily by alterations in mitochondrial oxidative phosphorylation (OXPHOS) protein/enzyme activity levels, which in turn increase mitochondrial reactive oxygen stress and adipocytes and pre-adipocyte apoptosis, and that these forces are heavily dependent on the intracellular concentration of these drugs. We further hypothesize that levels of OXPHOS proteins/enzyme activities in fat, peripheral blood mononuclear cells (PBMCs) or buccal cells (cheek swabs) will correlate with a decrease in limb fat content as assessed by dual energy x-ray absorptiometry (DEXA). Should these hypotheses be verified, there would be significant human health relevance in the understanding of the pathogenesis of HIV fat loss. Additionally, PBMCs' or buccal cells' OXPHOS protein/enzyme activities may serve as tools to monitor subjects preemptively for the risk of mitochondrial induced limb fat loss. We intend to evaluate adipose tissue, PBMCs, and buccal cells at baseline, wk 24, and wk 72 for mitochondrial OXPHOS protein/enzyme activity using a novel immunological assay and by immunohistochemistry, mtDNA copies/ cells, mitochondrial specific oxidative damage (8-oxo-deoxyguanine), and apoptosis. Additionally, PBMCs intracellular concentrations of ZDV, d4T, 3TC, FTC, and TDF triphosphates will be assessed for exposure-response relationships with mitochondrial toxicity.